1. Field of the Invention
This invention relates to therapy of ethanol withdrawal symptoms in individuals deprived of or abstaining from ethanol after ethanol intoxication. For convenience, the terms ethanol withdrawal symptoms and ethanol are used interchangeably with withdrawal symptoms and alcohol, respectively, throughout the text of this specification.
Prevention or suppression of withdrawal symptoms currently is part of therapeutic regimens directed at the cure of a clinical entity known as alcoholism. Although the latter is a complex disease comprising psychological as well as physical aspects, it always involves a varying degree of physical dependence on alcohol caused by a chronic abuse thereof. A common therapeutic regimen involves abstinence from ethanol to reverse the physical dependence thereon and treatment of withdrawal symptoms precipitated by such abstinence with a variety of drugs. Pentobarbital, chloral hydrate, paraldehyde and chlordiazepoxide are generally used to prevent or suppress such symptoms (Granville-Grossman, Recent Advances in Clinical Psychiatry, J. & A. Churchill Co., Ltd., London, pp. 129-139 [1971]). Although phenothiazines, such as promazine and chlorpromazine, are indicated in cases in which the physical dependence is moderate, their use is limited in severe cases and is ineffective to prevent delirium tremors or seizures (Thomas and Freedman, J. Am. Med. Ass'n., 188: 316 [1964]; and, Golbert et al., J. Am. Med. Ass'n., 201: 99 [1967]).
2. Description of the Prior Art
Levodopa is the trivial nomenclature for the naturally occurring compound, L-.beta.-3,4-dihydroxyphenylalanine. This compound is commercially available, and its synthesis has been reported in the literature (Yamada et al., Chem. Pharm. Bull., 10: 693 [1962]).
Known therapeutic uses of levodopa include treatment of the following disease entities: idiopathic and postencephalic parkinsonism, several extrapyramidal neuropathies, and depression.
The most widely recognized therapeutic use of levodopa is in the treatment of idiopathic and postencephalic parkinsonism (Cotzias et al., New Eng. J. Med., 276: 374 [1967]); and Yahr et al., Trans. Am. Neurol. Assn., 93: 56 [1968]). The mechanism of levodopa in the treatment of this disease is attributed to its presumed role in the correction of an imbalance of dopamine and acetylcholine in the basal ganglia, a biochemical defect associated with parkinsonism (Calne, Brit. Med. J., 2: 693 [1971]). The usual daily dosage of levodopa required to suppress the tremors of parkinsonism is from 4 to 5 g; a lower dose is effective if peripheral dopa decarboxylase inhibitors are administered in conjunction with levodopa. Examples of such peripheral dopa decarboxylase inhibitors which have been used with levodopa are: N'-(D,L-seryl)-N"-(2,3,4 -trihydroxybenzyl)hydrazine (Barbeau et al., Clin. Pharmac. Ther., 12: 353 [1971]); and .alpha.-methyl-dopa hydrazine (Cotzias et al., New Eng. J. Med., 280: 337 [1969]).
Levodopa also has been utilized to treat other extrapyramidal disorders such as those frequently observed after manganese poisoning (Mena et al., New Eng. J. Med., 282: 5 [1970]), supranuclear palsy (Klawans and Ringel, Europ. Neurol., 5: 115 [1971]), and hepatic coma (Parkes et al., Lancet 2: 1341 [1970]).
Therapeutic use of levodopa in the treatment of depression has been attempted but has proven to be of questionable value (Bunney et al., Lancet, 1: 885 [1969]; and Bunney et al., Lancet, 2: 352 [1970]).
In experiments attempting to implicate dopamine with sleep production in mice, a single dose of levodopa (400 mg/kg) produced a three-fold increase in sleeping time. However, this effect became smaller with increasing numbers of doses. Examination of brain catecholamines indicated an increasing shift of brain levels from dopamine to noradrenaline with increasing doses of levodopa. (Blum et al., Nature, 242: 407 [1973]).